Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale", Naples, Italy.
Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131, Naples, Italy.
J Immunother Cancer. 2019 Mar 29;7(1):91. doi: 10.1186/s40425-019-0569-1.
The therapeutic landscape in metastatic melanoma has changed dramatically in the last decade, with the success of immune checkpoint inhibitors resulting in durable responses for a large number of patients. For patients with BRAF mutations, combinations of BRAF and MEK inhibitors demonstrated response rates and benefit comparable to those from immune checkpoint inhibitors, providing the rationale for sequential treatment with targeted and immunotherapies and raising the question of optimal treatment sequencing.Biomarkers for the selection of anti-PD-1 therapy in BRAF wild type (BRAF WT) and in BRAF mutated (BRAF MUT) patients help development of alternative treatments for patients unlikely to benefit, and might lead to better understanding of the interaction of checkpoint inhibition and targeted therapy. In this paper we evaluate the performance of a previously developed serum proteomic test, BDX008, in metastatic melanoma patients treated with anti-PD-1 agents and investigate the role of BRAF mutation status. BDX008, a pre-treatment proteomic test associated with acute phase reactants, wound healing and complement activation, stratifies patients into two groups, BDX008+ and BDX008-, with better and worse outcomes on immunotherapy.Serum samples were available from 71 patients treated with anti-PD1 inhibitors; 25 patients had BRAF mutations, 39 were wild type. Overall, BDX008+ patients had significantly better overall survival (OS) (HR = 0.50, P = 0.016) and a trend for better progression-free survival (PFS) (HR = 0.61, P = 0.060) than BDX008- patients. BDX008 classification was statistically significant in the analyses adjusted for mutation status, LDH, and line of treatment (P = 0.009 for OS and 0.031 for PFS). BRAF WT BDX008+ patients had markedly long median OS of 32.5 months and 53% landmark 2 years survival, with statistically significantly superior OS as compared to BDX008- patients (HR = 0.41, P = 0.032). The difference between BDX008+ and BDX008- in PFS in BRAF WT patients and in OS and PFS in BRAF MUT patients did not reach statistical significance, though numerically was consistent with overall results. The test demonstrated significant interaction with neutrophil-to-lymphocyte ratio (NLR) (PFS P = 0.041, OS P = 0.004). BDX008 as a biomarker selecting for benefit from immune checkpoint blockade, especially in patients with wild type BRAF and in subgroups with low NLR, warrants further evaluation.
在过去的十年中，转移性黑色素瘤的治疗格局发生了巨大变化，免疫检查点抑制剂的成功应用使大量患者获得了持久的缓解。对于 BRAF 突变的患者，BRAF 和 MEK 抑制剂的联合治疗显示出与免疫检查点抑制剂相当的缓解率和获益，为靶向和免疫治疗的序贯治疗提供了依据，并提出了最佳治疗顺序的问题。BRAF 野生型（BRAF WT）和 BRAF 突变型（BRAF MUT）患者选择抗 PD-1 治疗的生物标志物有助于为不太可能获益的患者选择替代治疗，并可能有助于更好地了解检查点抑制与靶向治疗的相互作用。在本文中，我们评估了一种先前开发的血清蛋白质组学检测方法 BDX008 在接受抗 PD-1 药物治疗的转移性黑色素瘤患者中的表现，并研究了 BRAF 突变状态的作用。BDX008 是一种与急性期反应物、伤口愈合和补体激活相关的治疗前蛋白质组学检测方法，将患者分为 BDX008+和 BDX008-两组，在免疫治疗中具有更好和更差的结果。从接受抗 PD1 抑制剂治疗的 71 名患者中获得了血清样本；25 名患者有 BRAF 突变，39 名患者为野生型。总的来说，BDX008+患者的总生存期（OS）（HR=0.50，P=0.016）和无进展生存期（PFS）（HR=0.61，P=0.060）有显著改善趋势，优于 BDX008-患者。在调整突变状态、LDH 和治疗线的分析中，BDX008 分类具有统计学意义（OS 为 P=0.009，PFS 为 P=0.031）。BRAF WT BDX008+患者的中位 OS 显著延长至 32.5 个月，2 年生存率为 53%，与 BDX008-患者相比，OS 具有统计学显著优势（HR=0.41，P=0.032）。在 BRAF WT 患者中，BDX008+与 BDX008-在 PFS 方面的差异以及在 BRAF MUT 患者中在 OS 和 PFS 方面的差异未达到统计学意义，但在数值上与总体结果一致。该检测方法与中性粒细胞与淋巴细胞比值（NLR）之间存在显著的交互作用（PFS P=0.041，OS P=0.004）。BDX008 作为一种生物标志物，可选择从免疫检查点阻断中获益，特别是在 BRAF 野生型患者和 NLR 较低的亚组中，值得进一步评估。
